1. Field of the Invention
The present invention relates generally to the localized delivery of therapy to specific tissue structures in a patient. More particularly, the present invention relates to methods and apparatus for delivering therapeutic and diagnostic agents and other forms of therapy to a tissue structure while the tissue structure is isolated from systemic circulation.
Systemic chemotherapy for the treatment of cancer and other diseases can be effective, but suffers from a number of undesirable side-effects. Many chemotherapeutic agents are cytotoxic with selectivity for rapidly dividing neoplastic (cancerous) cells. It is desirable to use relatively high dosages of these agents in order to approach or achieve complete eradication of the cancerous cells. Such high dosages, however, can have a very harsh impact on the patient, including bone marrow toxicity, hair loss, nausea, fever, inability to digest food, and even death.
To lessen such systemic toxicity, isolated perfusion of organs and limbs with chemotherapeutic agents has been proposed. For example, limbs have been isolated from circulation using an externally applied tourniquet while an artificial blood circulation is maintained within the limb as the chemotherapeutic agent is administered. In another example, the liver has been isolated on the systemic venous side using a balloon catheter while a chemotherapeutic agent is injected into the liver. In a third example, a very complex shunt system has been surgically implanted for isolating the liver and recirculating oxygenated blood carrying a chemotherapeutic agent, as described in U.S. Pat. No. 4,192,302. Known methods, however, have not enabled complete isolation of an organ to eliminate the risks of systemic toxicity, with the ability to maintain localized circulation through the organ as well as systemic circulation to the remainder of the organism, by means of devices positioned solely through endovascular or less-invasive surgical access. Therefore, such methods have not gained wide acceptance for chemotherapy or other diagnostic and therapeutic procedures.
It would therefore be desirable to provide improved methods, systems, apparatus, and kits for the localized delivery of therapeutic agents, diagnostic agents, and other forms of therapy to organs and other tissue structures for the treatment and diagnosis of cancers and other diseases. Preferably, such systems will provide complete or substantially complete isolation of the organ or tissue structure. Both isolation and perfusion will preferably be achieved without major surgical incisions, more preferably via minimally invasive access routes, and most preferably via an endovascular access route through a peripheral or other connecting blood vessel to arteries or veins associated with the tissue structure. Isolation of the tissue structure should permit both total recirculation of blood or other oxygenated carrier within the tissue to be treated and alternatively once-through perfusion of the tissue. In all cases, it will preferably be possible to achieve tissue perfusion in either an antegrade, retrograde, or combination antegrade/retrograde manner. The present invention will meet these and other objectives.
2. Description of the Background Art
A shunt system for circulating a chemotherapeutic agent through the liver in an open surgical procedure is described in U.S. Pat. No. 4,192,302. Catheters and systems for the localized delivery of chemotherapeutic and other therapeutic agents are described in U.S. Pat. Nos. 5,411,479; 5,209,717; 5,135,474; 5,069,662; 4,883,459; 4,867,742; 4,820,261; 4,714,460; 4,345,588; and PCT Application WO 94/22519. Intravascular and other drug delivery catheters are described in U.S. Pat. Nos. 5,599,307; 5,556,389; 5,505,700; 5,328,470; 5,167,628; 5,163,905; 5,087,244; 5,007,897; and 4,540,402. Intravascular bypass catheter systems are described in U.S. Pat. Nos. 5,478,309; 5,458,574; and 5,451,207. A catheter for hyperthermic treatment of a lung malignancy employing a perfluorocarbon medium is described in U.S. Pat. No. 5,158,536. Isolated organ and limb perfusion is discussed in Wang et al. (1996) Int. J. Radiation Oncology Biol. Phys. 34:309-311; Fajimura et al. (1995) Hepato-Gastroenterology 42:878-884; Matsuzaki et al. (1995) Ann. Thorac. Surg. 59:127-131; Pogrebniak et al. (1994) Ann. Thorac. Surg. 57:1477-1483; Turrisi 91993) Chest 103:565-595; Fried et al. (1993) J. Extra-Corpor. Tech. 25:22-26; Watanabe et al. (1990) Jpn. J. Surg. 20:27-35; Minchin et al. (1984) J. Pharmacol. Exp. Therap. 229:193-198; and Johnston et al. (1983) Cancer 52:404-409.
The present invention provides improved methods, systems, apparatus, and kits for the isolated perfusion of organs and other tissue structures. The systems, including multiple catheters as described in more detail below, can provide for partial or complete isolation of the vasculature of a tissue structure from the remainder of the patient""s circulatory system. By providing such isolation, the vasculature within the tissue structure may be perfused with a desired therapeutic or diagnostic agent, with added or varied concentrations of oxygen, typically via recirculation of blood or other oxygen-carrying medium through the vasculature of the tissue structure with minimum or no loss of the agent into systemic circulation. Perfusion and/or recirculation may be achieved in an antegrade direction, a retrograde direction, or some combination of antegrade and retrograde directions. Additionally, various parameters within the isolated organ, such as temperature, pressure, chemical concentrations, and vascular permeability, may be adjusted for maximum local effect without systemic effect. Thus, the apparatus and methods of the invention enable the perfusion of organs and other tissue structures with therapeutic agents which are currently unavailable for systemic delivery due to their toxicity, as well as perfusion with currently-utilized therapeutic agents, but at such dosage levels, pressures, and temperatures or under such other conditions that systemic delivery would be harmful.
Methods according to the present invention preferably rely on first isolating the tissue structure from the patient""s circulatory system and then delivering a therapeutic agent to the tissue structure. The tissue structure is isolated by endovascularly positioning a first catheter in an artery which supplies blood to the tissue structure and, preferably, deploying a first occluding member on or over the catheter to occlude the artery. A second catheter is endovascularly positioned in a vein to which blood drains from the tissue structure and deploying a second occluding member on or over the second catheter to occlude the vein. The therapeutic or diagnostic agent is then perfused through the vasculature of the tissue structure via at least one of the first and second catheters, while blood circulation continues through the remainder of the patient circulatory system and the vasculature of the tissue structure remains isolated from the circulatory system. In some cases it may not be necessary to occlude the artery supplying blood to the target organ, since the direction of blood flow into the organ will inhibit leakage of the therapeutic agent into the remainder of the arterial system. However, in most cases occlusion of both the arteries supplying blood to the organ and veins draining blood from the organ will be preferred so as to enable total isolation and perfusion of the organ without risk of systemic effects. As used herein, the term xe2x80x9cisolatingxe2x80x9d may be used to mean complete isolation of an organ, by occluding all arteries supplying blood to the organ and all veins draining blood from the organ, or for partial isolation of the organ, wherein only some of such arteries and/or veins are occluded. Thus, the invention may be used to reduce normal circulation through the organ by, for example, as little as 30%-50%, preferably by 60%-80%, and most preferably by as much as 100%.
Usually, only those blood vessels which supply blood to the organ or other tissue structure for maintaining viability of that tissue will be isolated. That is, blood vessels which supply blood to an organ for processing by the organ will usually remain patent. In some instances, however, it may be desirable to also occlude those blood vessels which supply and drain blood from an organ for processing as well. Additionally, in some cases the methods of the invention may involve occlusion of other fluid vessels communicating with an organ, such as lymph ducts, bile ducts, the airways of the lungs, the urinary tract, or digestive tract. By xe2x80x9cendovascularly positioning,xe2x80x9d it is meant that the catheters are introduced through a remote blood vessel or other type of vessel, usually a peripheral blood vessel, and guided to the target artery or vein intravascularly, typically over a guidewire or by other conventional intravascular placement techniques.
The occluding member(s) will typically be positioned on the catheter at a location which permits deployment when a port or other passage on the catheter is located within the target artery or vein at a desired position. Alternatively, the occluding members may be deployed in a larger artery or vein from which the target artery or vein branches. In this case, a pair of spaced-apart occluding members may be utilized on the catheter to occlude the larger artery or vein on either side of the branching target vessel. The occluding member is preferably an inflatable balloon, but it could also be a variety of other deployable elements, such as flanges, umbrellas, collapsible valves, flapper valves, pivoting disk valves, expandable coated mesh elements, or the like. The occluding member could also be deployed separately from the catheter, such as an externally deployed clamp or snare which may be placed over a blood vessel to externally seal the blood vessel against the catheter. Such external clamps could be placed using an open surgical technique, but would more usually be placed using minimally invasive techniques employing cannulae or trocar sleeves and indirect vision, e.g. an endoscope and associated video display.
The catheters and methods of the invention may also be used to isolate portions of an organ for even more specific isolation and perfusion of therapeutic agent. Additionally, for bilateral organs having bilateral (right and left) arterial supply and venous drainage systems such as the lungs, kidneys, prostate, stomach, ovaries, and testicles, the methods of the invention may be used for either unilateral or bilateral isolation and perfusion by subselecting the vessels on the right side, left side or both for occlusion and perfusion. Further, it may be desirable in some instances to perfuse the organ unilaterally and collect the agent bilaterally, in the event of any communication between the vasculature of the two sides.
Preferably, the methods of the present invention further comprise collecting the therapeutic agent through at least one of the first and second catheters while the tissue structure remains isolated and the perfusate continues to be delivered. In this way, a complete perfusion of the vasculature of the tissue structure can be achieved. Optionally, the therapeutic agent may be delivered through more than one catheter and/or collected through more than one catheter in order to enhance both the rate and completeness of the perfusion. By delivering the perfusate through the first catheter into the arterial side of the tissue structure and collecting the agent through the second catheter on the venous side of the tissue structure, antegrade perfusion can be established. Conversely, by delivering the therapeutic agent through the second catheter on the venous side of the tissue structure and collecting the therapeutic agent through the first catheter on the arterial side, retrograde perfusion can be established. In some instances, when more than two catheters are utilized, combinations of antegrade and retrograde perfusion can be performed simultaneously or sequentially.
As a further alternative method, perfusate may be delivered by either the first or second catheter individually, and collected by the same catheter by applying negative pressure through its lumen. Preferably, the perfusate is allowed to dwell in the organ for a period of time to maximize therapeutic effect, during which time the balloon on the delivery catheter prevents blood from flushing the perfusate from the organ. In this way, a single catheter may be used to isolate and perfuse all or a portion of an organ.
The tissue structure will usually be an organ, preferably being selected from the group consisting of the brain, lungs, breast, kidneys, liver, spleen, stomach, small and large bowel, pancreas, colon, bladder, thyroid gland, uterus, prostate, testicles, ovaries, and the like. The perfusate may comprise a variety of active agents, including therapeutic agents, diagnostic agents, sensitizing agents, potentiating agents and combinations thereof. Exemplary diagnostic agents include radio nucleotides, labelled antibodies, dyes, contrast media, and other diagnostic materials of the type which are generally delivered systemically but which could benefit from isolated organ-specific or tissue-specific delivery. Useful therapeutic agents include drugs, biologic materials, and the like. Exemplary chemotherapeutic drugs include adriamycin, methotrexate, taxol, bleomycin, and the like. Biologic treatments include antibodies, nucleic acids (for gene therapy), proteins, cellular materials, growth factors, and the like. In particular, the methods and systems of the present invention may be usual for performing cellular transplantation. For example, in a patient whose liver has been damaged by chemotherapy or other causes, it will be possible to infuse hepatic cells back into the isolated liver, typically with growth factors, nutrients, and the like, in order to promote regeneration of the liver.
In addition, the methods of the invention may be used to regulate various other parameters of blood or fluids in an organ including temperature, hydrostatic pressure, osmotic or oncotic pressure and regional fluid volume within the organ. Such parameters may be altered to control or enhance uptake or effectiveness of a particular drug, sensitizing or potentiating agent, dye or marker, to facilitate visualization of the organ (using X-ray, magnetic resonance imaging, light or ultrasound), or to otherwise alter biochemical processes within the organ. Further, the oxygen concentration within the blood or fluid in the organ may be varied for enhanced therapeutic effect. In some cases, the effectiveness of a particular drug may be enhanced by delivering it with an oxygen rich fluid, while with other drugs, a hypoxic environment may be created to enhance a drug""s effectiveness.
In a preferred aspect of the method, the delivering step will comprise delivering both the therapeutic agent and an oxygenated vehicle or carrier to the tissue structure. It will be appreciated that isolation of the tissue structure from a patient""s circulation may deprive the tissue structure of blood and oxygen. While oxygen deprivation will not always be a problem, in at least some instances provision of oxygen to the tissue structure can permit significant lengthening of the treatment protocol. Without continuing oxygenation of the tissue structure, treatment will in some cases be limited to a period of time less than 60 minutes, usually less than 30 minutes, depending upon the particular organ being treated. By delivering the therapeutic agent together with an oxygenated vehicle, the treatment times can be extended significantly, typically to a period longer than 60 minutes, often to a period longer than two hours, and sometimes for a period of four hours, or longer. Treatment periods may be even longer if the target organ and/or the entire organism is cooled during treatment. Thus, the invention enables significantly longer periods of treatment or diagnosis than can be tolerated with systemic administration of toxic agents. However, in the case of some drugs, therapeutic effect may be enhanced by inducing hypoxia in the target tissue. Thus, in some cases, delivery of the therapeutic agent in an oxygen-depleted medium will be preferred.
The oxygenated vehicle may comprise a synthetic oxygen carrier, such as a perfluorocarbon or other blood substitute material. More usually, however, the oxygenated vehicle will be oxygenated blood, typically blood withdrawn and recirculated from the patient being treated. In particularly preferred protocols, blood will be obtained from the patient, combined with a therapeutic and/or diagnostic agent, and the resulting combination perfused through the catheter(s) into and through the tissue structure. Most preferably, the perfused blood, synthetic oxygen carrier, or combination of blood and synthetic carrier will then be collected through one or more of the other catheters, reoxygenated, usually filtered, and returned to the vasculature of the tissue structure, typically in a recirculating manner. Optionally, the blood and/or synthetic oxygen carrier could be superoxygenated. While less preferred, it will also be possible to recirculate and reoxygenate synthetic oxygen carriers. It will also be possible to utilize both the synthetic oxygen carriers and patient (autologous) or heterologous blood in a once-through manner, where the vehicle is collected and then disposed.
In a most preferred aspect, the therapeutic agent delivering step comprises establishing extracorporeal recirculation through the vasculature of the isolated tissue structure. In particular, the establishing step comprises delivering a medium comprising the therapeutic agent and blood or other oxygen carrier through one of the catheters. The medium is then collected through another of the catheters after the medium has perfused at least a portion of the tissue structure. The collected medium is then extracorporeally pumped back through the first catheter after it has been oxygenated. Usually, the medium is filtered after it is collected and before it is returned to the patient. Optionally, therapeutic agent will be continuously or intermittently introduced to the medium as it is being extracorporeally recirculated.
In another aspect of the present invention, a medium of the therapeutic agent and an oxygen carrier may be provided, typically in a relatively large volume. The medium may then be delivered to the tissue structure through one of the catheters and collected after it has perfused the tissue structure from another of the catheters. Optionally, the medium may be allowed to dwell in the organ for a desired period of time before collection to optimize therapeutic effect. The medium will not be recirculated.
An additional method of treatment of a tissue structure according to the invention comprises endovascularly occluding an artery and a vein and endovascularly delivering a therapeutic agent to the tissue structure at a systemically toxic concentration or dose, the systemically toxic concentration or dose being substantially greater than, usually at least 1.5 times, frequently at least 2 to 10 times, and preferably up to 100 times the concentration or dose clinically acceptable for systemic delivery. As used herein the term xe2x80x9cclinically acceptable for systemic deliveryxe2x80x9d means that concentration or dose of the therapeutic agent which is approved by the US Food and Drug Administration or other relevant regulatory body, or if such approval is not applicable to such therapeutic agent, the concentration or dose which is recommended by the manufacturer of such therapeutic agent, or in the absence of such recommendation, then the concentration or dose which is generally accepted for systemic delivery without isolation of the target organ according to currently published literature in the relevant field. In this way, the invention enables therapeutics to be delivered to an isolated organ which are too toxic for systemic delivery. The optimal dose delivered will be determined by a number of factors, including the degree of response in the tumor, necrosis or injury to healthy tissue in the target organ, immunologic responses and the creation of other adverse effects. Moreover, the invention enables therapeutic agents to be delivered at the dosage levels currently used for systemic administration, but with greatly reduced or eliminated adverse systemic effects.
Still another method of treatment of a tissue structure comprises delivering a therapeutic agent to the tissue structure; and heating the tissue structure during the delivering step so as to increase cellular uptake or efficacy of the therapeutic agent. During delivery or recirculation of the therapeutic agent, an organ may be heated to a temperature in excess of normal body temperature (98.6xc2x0 F.) to a point higher than what might be tolerated systemically, e.g. higher than 100xc2x0 F., preferably 101-105xc2x0 F., more preferably 106-110xc2x0 F., and in some cases 110-120xc2x0 F. Usually the organ will be heated by first heating the therapeutic agent before it is delivered such that heat is transferred from the therapeutic agent to the organ upon delivery. Additionally, it may be desirable to utilize heating and cooling to create temperature differences between various structures so as to enhance the selectivity of the therapeutic agent. For example, certain organs targeted for therapy may be heated to enhance efficacy of the agent delivered, while other organs are cooled to inhibit the therapeutic effect of the agent in such organs. Further, heating or cooling an isolated organ may have therapeutic effects even without delivering any therapeutic agent. This may be accomplished by delivering or recirculating heated or cooled saline or other suitable fluid through the organ using the catheters and methods described herein to raise or lower the organ temperature for a desired time period.
In a first exemplary method according to the present invention, the tissue structure is a lung, the first catheter occludes a pulmonary artery, the second catheter occludes a superior pulmonary vein, and a third catheter occludes an inferior pulmonary vein. Alternatively, or additionally, the method may further comprise occluding the pulmonary venous ostia in the left atrium, individually or together by means of a diaphragm extending around both ostia. The second and third catheters may be introduced from the venous side via a transseptal puncture, or from the arterial side via the aorta, aortic valve and mitral valve. The therapeutic agent may be delivered through the first catheter and collected in at least one of the second and third catheters to establish antegrade perfusion. Alternatively, the therapeutic agent may be delivered through at least one of the second and third catheters and collected in the first catheter to establish retrograde perfusion. In another alternative method, only the first catheter is used and the therapeutic agent is delivered into the pulmonary artery, allowed to dwell in the lungs while the first balloon occludes the pulmonary artery to prevent flushing, then collected through the first catheter. Similarly, only the second and third catheters may be used to deliver the therapeutic agent in a retrograde manner into the pulmonary veins, and the same two catheters used to collect the agent from the pulmonary veins. Additionally, the first catheter may have at least two balloons at spaced apart locations near the catheter""s distal end to facilitate occlusion of the pulmonary artery on opposing sides of one or more branching arteries, thereby allowing selective perfusion of particular regions of the lung.
The method of isolated perfusion of the lung may be further enhanced by concurrent delivery of a therapeutic agent, sensitizing agent, potentiating agent, bronchial blocker, steam, solvent, or other suitable substance into the airways of the lung via the bronchus. For example, vasomotor tone may be modified by altering the gas mixture in the lung, thereby altering local pulmonary circulation and enhancing selectivity of the therapeutic agent to the target lung tissues. Selective ventilation of the lung may also be used to induce hypoxia in selected regions, thereby stimulating pulmonary vasoconstriction in such regions so as to reduce uptake of the therapeutic agent delivered via the pulmonary artery. Vasodilating agents or vasoconstricting agents may be delivered into selected regions of the lungs to alter pulmonary vasoconstriction. Hot or cold fluids may also be introduced to alter vasoconstriction or other parameters. Thus, the method of the invention may further include positioning a delivery tube into a bronchus via the trachea and delivering a therapeutic, diagnostic, sensitizing, or potentiating agent, and/or air, oxygen, carbon dioxide or other fluids, into the lung through the delivery tube. The delivery tube may include an occluding member (e.g. balloon) for occluding the bronchus to maintain the therapeutic agent in the lung. The delivery tube and occluding member may further be positionable in selected branches of the bronchial tree to allow for subselection of a particular region of the lung. The agent may be evacuated from the lung by applying negative pressure to the delivery tube.
In a second exemplary method according to the present invention, the tissue structure is a liver, the first catheter occludes a hepatic artery, the second catheter occludes a hepatic vein, and a third catheter occludes a portal vein. The therapeutic agent may be delivered through at least one of the first and third catheters and collected in the second catheter to establish antegrade perfusion. Alternatively, the therapeutic agent may be delivered through the second catheter and collected in at least one of the first and third catheters to establish retrograde perfusion. The portal vein is preferably catheterized by introducing the third catheter through a transhepatic puncture into the portal vein or branch thereof within the liver. The third catheter may be introduced into the liver either endovascularly from the inferior vena cava and a hepatic vein, or transabdominally from an abdominal incision directly into the liver.
In a third exemplary method according to the present invention, the tissue structure is a brain, the first catheter occludes an internal carotid artery, a third catheter occludes another internal carotid artery, the second catheter occludes an internal jugular vein, and a fourth catheter occludes another internal jugular vein. By occluding these arteries and veins, an anterior segment of the brain is isolated from patient circulation. Alternatively or additionally, a posterior segment of the brain may be isolated by placing a first (or fifth) catheter to occlude a vertebral artery, a second (or sixth) catheter to occlude another vertebral artery, a third (or seventh) catheter to occlude vertebral vein, and a fourth (or eighth) catheter to occlude another vertebral vein. In either case, by delivering the therapeutic agent through at least one of the catheters positioned within an artery and collecting the perfused agent from at least one of the catheters positioned in a vein, antegrade perfusion of the anterior, posterior, or both segments of the brain may be established. Alternatively, by delivering the therapeutic agent through at least one of the catheters positioned in a vein and collecting the perfused agent from at least one of the catheters positioned in an artery, retrograde perfusion of the brain may be established.
In a fourth exemplary method according to the present invention, the tissue structure is a prostate, the first catheter occludes an inferior vesical artery, and the second catheter occludes an inferior vesical vein. Optionally, a third catheter may be positioned to occlude an internal pudendal artery and/or a fourth catheter may be positioned to occlude an internal pudendal vein. In both cases, the therapeutic agent may be delivered through at least one of the catheters positioned in an artery and collected from at least one of the catheters positioned in a vein to establish antegrade perfusion. Alternatively, the therapeutic agent may be delivered through at least one of the catheters positioned in a vein and collected from at least one of the catheters positioned in an artery to establish retrograde perfusion.
In a fifth exemplary method according to the present invention, the tissue structure is a kidney, the first catheter occludes a renal artery, and the second catheter occludes a renal vein. The therapeutic agent may be delivered through the first catheter and collected from the second catheter to establish antegrade perfusion. Alternatively, the therapeutic agent may be delivered through the second catheter and collected from the first catheter to establish retrograde perfusion.
Additional methods of the invention include isolation and perfusion of:
The bowel, by occluding the superior or inferior mesenteric arteries and the portal vein;
The stomach, by occluding the gastric arteries, and/or other arterial sources, along with the portal vein;
The spleen, by occluding the splenic artery and the portal vein;
The pancreas, by occluding the appropriate branch of the celiac artery and the portal vein;
The testicles or ovaries by occluding the testicular or ovarian arteries and the testicular or ovarian veins;
The pelvic organs such as the uterus, rectum or the bladder, by occlusion of the internal iliac artery or arteries branching therefrom which supply blood to the target organ, and occlusion of the internal iliac vein or veins branching therefrom into which blood from the target organ drains.
Systems according to the present invention comprise at least a first catheter configured for endovascular introduction through a peripheral blood vessel to an inlet artery or other blood vessel supplying blood to the vasculature within the tissue structure. The first catheter may have a first occluding member disposed near its distal end and a first inner lumen extending longitudinally therethrough to a first opening distal to the occluding member. The occluding member is configured to selectively occlude the inlet artery, typically being an inflatable balloon, or mechanical occlusion element such as an umbrella or coated tubular mesh. Alternatively, the system may employ an occluding member which is separate from the catheter, e.g. a loop or snare which may be positioned externally about the blood vessel in which the catheter is placed. By then cinching or otherwise closing the loop or snare against the blood vessel, a lumen of the blood vessel can be isolated so that blood or other media does not flow in an antegrade or retrograde direction past the catheter. Such loops, snares, or other external occlusion devices will typically be placed percutaneously through a small cannula or incision typically while viewing the blood vessel endoscopically on a video monitor. It will also be possible, although generally less preferred, to make a larger surgical incision and place the external occlusion device using more conventional open surgical procedures.
The system further comprises a second catheter configured for endovascular introduction through a peripheral blood vessel to an outlet vein or other blood vessel to which blood flows from the vasculature of the tissue structure. The second catheter may also include an occluding member and a lumen therethrough. Alternatively, the second catheter may be used with a separate, external occlusion device of the type described above in connection with the first catheter. Optionally, the system may include third, fourth, fifth, sixth, seventh, eighth, or possibly more catheters configured for introduction to and occlusion of additional arteries and veins having flow connections to the vasculature of the tissue structure. The system will also include a source of therapeutic agent coupled to a lumen of at least one of the catheters for delivering the therapeutic agent to the tissue structure.
The source of therapeutic agent may comprise only the agent present in a conventional, non-oxygenated carrier, such as saline, glucose, or the like. Preferably, however, the source of therapeutic agent will also comprise an oxygen carrier for delivering oxygen through one or more of the catheters together with the therapeutic agent. Still further preferably, the source of therapeutic agent will comprise a recirculating and oxygenating system for establishing extracorporeal flow between at least two of the catheters and often between more than two of the catheters. The recirculating system may be coupled to the source of therapeutic agent so that the agent may be continuously or intermittently introduced into the recirculating medium. Usually, the recirculating system will comprise at least a pump and an oxygenator, and may optionally comprise further components such as filter, bubble trap, reservoir, or other components of a type which are used in conventional cardiopulmonary bypass circuits. The recirculating system will preferably include an oxygen regulator to allow the oxygen concentration in the circulating medium to be regulated, enabling the delivery of oxygen-rich, oxygen-poor, or normally oxygenated fluids to the organ for optimum therapeutic effect.
As an alternative, the therapeutic agent source may comprise a container for holding a pre-selected volume of an oxygenated medium comprising the therapeutic agent and a separate receptacle for collecting the medium after it has been perfused through the tissue structure. The container of fresh medium may thus be connected to one or more of the catheters to deliver the medium to the vasculature of the tissue structure while the receptacle may be connected to other(s) of the catheters to collect the medium after it has perfused the tissue.
Apparatus according to the present invention still further comprise kits including catheter sets with individual catheters selected for accessing and perfusing particular organs. The kits will include at least one catheter, usually at least two catheters, and frequently including three or more catheters (as described above), where all the catheters comprise a catheter body having a proximal end, a distal end, and a lumen therethrough. An occluding member is preferably disposed near the distal end of the catheter, typically being an inflatable balloon, and each of the catheters is adapted for endovascular introduction through a peripheral blood vessel to position the occluding member within a target blood vessel selected to isolate the desired organ. Alternatively, external occlusion device(s) may be provided which are adapted for externally clamping, cinching, or otherwise closing the blood vessel over the catheter while the catheter is positioned in the lumen of the blood vessel.
Kits may further comprise instructions for use setting forth a method for delivering a medium comprising a therapeutic agent through at least one of the catheters. Generally, the instructions describe one of the methods described herein. Usually, the method set forth in the instructions further comprises collecting the medium through another of the catheters after the medium has perfused the tissue structure. The method set forth in the instructions may still further comprise extracorporeally recirculating and oxygenating the medium from the other catheter before it is returned to the first catheter. The instructions for use may further set forth concentrations, dosages, frequencies of administration, temperatures, pressures, and other information concerning the agent to be delivered. Because the devices and methods of the invention permit complete isolation of a target tissue structure, agents which are unsafe for systemic delivery may be utilized, and known agents may be delivered in a way which might be toxic or otherwise harmful if delivered systemically using conventional techniques. Often, the catheters and instructions are packaged together in a common container, such as a pouch, box, tray, tube, or the like.
A first kit for isolated perfusion of a lung comprises at least two catheters. A first catheter is configured to position the occluding member within a pulmonary artery. A second catheter is configured to position the occluding member within or over at least one of the pulmonary veins. Usually, two catheters are used to occlude the pulmonary veins, the second catheter being configured to position the occluding member in the superior pulmonary vein, and a third catheter being configured to position the occluding member within an inferior pulmonary vein. Alternatively, a single catheter with a diaphragm may be used for occluding both pulmonary veins. The kit may further include a delivery tube positionable in a bronchus for delivering a therapeutic agent into the airways of the lung.
A second kit for isolated perfusion of a liver comprises at least three catheters. A first catheter is configured to position the occluding member within a hepatic artery. A second catheter is configured to position the occluding member within a hepatic vein. A third catheter is configured to position the occluding member within a portal vein.
A third kit for isolated perfusion of a brain comprises at least four catheters. In a first embodiment, a first catheter is configured to position the occluding member within a left internal carotid artery. A second catheter is configured to position the occluding member within a right internal carotid artery. A third is configured to position the occluding member within a left internal jugular vein. The fourth catheter is configured to position the occluding member within a right internal jugular vein. Use of these four catheters will isolate an anterior segment of the brain. In a second embodiment, the first catheter is configured to position the occluding member within a left vertebral artery, the second catheter is configured to position the occluding member within a right vertebral artery, the third catheter is configured to position the occluding member within a left vertebral vein, and the fourth catheter is configured to position the occluding member within a right vertebral vein. Use of the second exemplary kit embodiment will isolate a posterior segment of the brain. A kit may further be provided comprising all eight catheters of both the first and second embodiments for substantially total isolation of the vasculature of the brain.
A fifth kit for isolated perfusion of a prostate comprises at least two catheters. The first catheter is configured to occlude the left or right inferior vesical artery. The second catheter is configured to occlude the left or right inferior vesical vein. Optionally, the kit may comprise a third catheter configured to occlude a left or right internal pudendal artery, and a fourth catheter configured to occlude a left or right internal pudendal vein. The method may be augmented by isolating the ostia of the prostate glands in the urethra using a trans-urethral catheter to allow collection or delivery of agents to the prostate via the prostate glands.
A sixth kit according to the present invention for isolated perfusion of a kidney comprises at least two catheters. The first catheter is configured to position the occluding member within a renal artery, and the second catheter is configured to position the occluding member within a renal vein.
A seventh kit according to the invention for isolated perfusion of a stomach comprises at least two catheters. The first catheter is configured to position an occluding member within a gastric artery, and a second catheter is configured to position the occluding member within the portal vein, or in a hepatic vein.
An eighth kit according to the invention for isolated perfusion of a spleen comprises at least two catheters. The first catheter is configured to position an occluding member within a splenic artery, and a second catheter is configured to position the occluding member within the portal vein, or in a hepatic vein.
A ninth kit according to the invention for isolated perfusion of a small bowel comprises at least two catheters. The first catheter is configured to position an occluding member within a superior mesenteric artery, and a second catheter is configured to position the occluding member within the portal vein, or in a hepatic vein.
A tenth kit according to the invention for isolated perfusion of a large intestine comprises at least two catheters. The first catheter is configured to position an occluding member within a inferior mesenteric artery, and a second catheter is configured to position the occluding member within the portal vein, or in a hepatic vein.
An eleventh kit according to the invention for isolated perfusion of a pelvic organ such as the uterus or the bladder comprises at least two catheters. The first catheter is configured to position an occluding member within an internal iliac artery, and a second catheter is configured to position the occluding member within an internal iliac vein.
A twelfth kit according to the invention for isolated perfusion of a testicle or ovary comprises at least two catheters. The first catheter is configured to position an occluding member within a testicular or ovarian artery, and a second catheter is configured to position the occluding member within a testicular or ovarian vein.
It will be understood that many of the organs and tissue structures susceptible to treatment using the apparatus and methods of the invention have bilateral (left and right) arterial and venous systems, as well as, in some cases, superior and inferior arterial and venous systems, anterior and posterior arterial and venous systems, and other vascular subsystems. It will be understood that the apparatus and methods of the invention may be used to isolate and perfuse any or all of such subsystems simultaneously or independently by subselecting the particular arteries and veins within each vascular subsystem. Thus, for example, the anterior or posterior portion of the brain, left or right lung, left or right kidney, left or right testicle or ovary, and the left or right side of the prostate, uterus, rectum, or stomach, or any subselectable region thereof, may be isolated and perfused individually or together with other regions.
Any of the apparatus and methods described above may be further enhanced by isolated perfusion of lymphatic system. Therefore, the invention further provides an apparatus for isolated perfusion of the lymphatic system comprising at least one catheter configured to position an occluding member in a lymphatic duct selected from the thoracic duct and the right lymphatic duct. Alternatively, the invention provides at least one catheter having at least two occlusion members for isolating an ostium of a lymphatic duct from a vein, usually a subclavian vein.
Some of the apparatus and methods described above, such as those for the liver, kidney, spleen, pancreas, bowel, and stomach, may further benefit from the isolated perfusion of the bile ducts. The invention further provides apparatus and methods for isolated perfusion of the bile ducts. In one embodiment, the apparatus comprises at least one catheter for positioning at least one occluding member into a bile duct. The catheter may be positioned transhepatically, or transesophageally via the duodenum, into, for example, the common bile duct, or the pancreatic duct.